Complex regional pain syndrome (CRPS) is an especially difficult medical problem because it is a chronic disease affecting a patient's quality of life, often with no effective treatment. Therefore, it is important to understand the mechanisms of CRPS, thereby allowing new treatment paradigms to be developed, which is the long-term goal of this proposal. Using the spinal nerve ligation model, an extensively used rat model of CRPS (type II with major nerve injury), various aspects of the peripheral mechanisms of CRPS has been studied in the past, with support from the present grant. In the upcoming funding period of the present grant, however, the focus will be on spinal mechanisms of CRPS. The overall hypothesis is that spinal nerve injury induces a sustained elevated level of highly toxic free radicals, reactive oxygen species (ROS), in the spinal cord, leading in turn to central sensitization of dorsal horn neurons, which is the key underlying mechanism in CRPS. Four specific aims are proposed to test the following individual hypotheses: 1) that spinal nerve ligation induces an elevated level of spinal ROS, 2) that the increased ROS are associated with central sensitization and behavioral signs of pain, 3) that an important mechanism of ROS-induced central sensitization is impairment of GABA function in the cord, and 4) that as time passes many dorsal horn neurons die due to extended exposure to ROS. The present proposal is to test these hypotheses using a multidisciplinary approach. Successful completion of these aims will not only uncover important spinal mechanisms of CRPS but may also lead to the development of new analgesic drugs based on free radical scavengers.